Cleavable solid dosage forms and method for the production thereof

ABSTRACT

Solid, elongate dosage forms ( 10 ) with a long axis ( 11 ) and with a length (L) which is defined by projection of the ends ( 12, 13 ) of the dosage form to the long axis, where a cross-sectional area ( 14, 15, 16 ) oriented perpendicular to the long axis ( 11 ) has an area which is variable along the long axis ( 11 ) and increases from a cross-sectional area ( 15 ) which is located between the ends ( 12, 13 ) and has a minimal area essentially continuously toward the two ends ( 12, 13 ) up to in each case a cross-sectional area ( 14  and  16  respectively) with a maximal area, wherein the distance of the maximal cross-sectional area ( 14 ) which is located near one end ( 12 ) from the maximal cross-sectional area ( 16 ) which is located near the other end ( 13 ) is, projected on the long axis ( 11 ), more than half the length (L) of the dosage form ( 10 ), are described.

This application is a 371 of PCT/EP99/09403 filed Dec. 3, 1999.

The present invention relates to divisible solid dosage forms, inparticular solid pharmaceutical dosage forms, and to a process for theirproduction.

It is often desirable for solid pharmaceutical dosage forms, for exampletablets, to be divisible in order to be able to alter the dosage withoutthe need to produce individual tablets for each particular dosage.Division of a tablet into accurately predetermined parts makes itpossible to administer a fraction or any multiple of the fraction of theactive ingredient present in the tablet.

To facilitate division, tablets normally have scores. The tablet isbroken apart by exerting pressure on the tablet, with the tablet beingheld between two fingers or with both hands. Divisible tablets aredescribed, for example, in CH 683 066 or U.S. Pat. No. 3,927,194.

DE-B 30 30 622 describes a divisible tablet with controlled and delayedrelease of active ingredient. The ratio of length to width to height inthis case is intended to be about 2.5-5:about 0.9-2:1. One or morerelatively deep score(s) running perpendicular to the length and to theheight are present. The bottom and top surfaces are, independently ofone another, flat or curved convexly around the long axis or parallelsthereto.

DE-B 44 46 470 describes a process for producing divisible tablets byshaping an active ingredient-containing melt in a calender with twocounter-rotating molding rolls which have depressions for receiving andmolding the melt to tablets, where the depressions are divided by atleast one bar which extends essentially as far as the surface of themolding roll and forms a score.

One problem with the known divisible solid dosage forms is thatexpenditure of a relatively large force is necessary to divide thedosage forms. This problem is particularly pronounced with dosage formsproduced by melt extrusion because they usually consist of a very hardand brittle material. Attempts have been made to bypass this problem byproviding the solid dosage forms with very deep notches with large notchangles. However, with these approaches to a solution there is the riskthat the solid dosage form will break during after-treatment steps, e.g.during deflashing or film-coating, due to the stress on the material,which leads to a large proportion of rejects.

A further serious problem with known divisible solid dosage forms is theinadequate uniformity of mass of the manually divided halves of thedosage forms. Corresponding investigations have revealed standarddeviations of between 3 and 13% for the tablet halves (see H. G.Kristensen et al., Pharmeuropa, Volume 7, No. 2, June 1995, pp. 298 etseq.). Standard deviations as high as this lead to inaccurate dosages,which is particularly undesirable with active ingredients of highactivity. The inadequate uniformity of mass of the manually dividedtablet halves derives, on the one hand, from the fractures area notbeing exactly at the intended place and, on the other hand, from thetendency of the tablet material to escape at outer edges of the tabletmold, which leads to losses of active ingredient.

It is an object of the present invention to provide solid dosage formswhich display easy divisibility and, at the same time, a sufficientresistance to stress for further processing steps. It was additionallyintended that the solid dosage forms be of a nature such that thefragments resulting from manual division of the solid dosage formsdisplay a maximum uniformity of mass.

We have found that this object is achieved by the solid dosage formshaving a particular geometry. The present invention therefore relates toa solid, elongate dosage form (10) with a long axis (11) and with alength (L) which is defined by projection of the ends (12, 13) of thedosage form onto the long axis, where a cross-sectional area (14, 15,16) oriented perpendicular to the long axis (11) has an area which isvariable along the long axis (11) and increases from a cross-sectionalarea (15) which is located between the ends (12, 13) and has a minimalarea essentially continuously toward the two ends (12, 13) up to in eachcase a cross-sectional area (14 and 16 respectively) with a maximalarea, wherein the distance of the maximal cross-sectional area (14)which is located near one end (12) from the maximal cross-sectional area(16) which is located near the other end (13) is, projected on the longaxis (11), more than half the length (L) of the dosage form (10).

FIG. 1 shows a dosage form according to the invention in cross section.

FIG. 2 shows a depression in the molding roll of a molding calender withwhich the dosage forms according to the invention can be obtained.

FIG. 3 shows a dosage form according to the invention which can beobtained using a molding roll with depressions of the type shown in FIG.2.

The long axis referred to here is the principal axis of inertia of thesolid dosage form on which the projection of the dosage form has thegreatest extent. This extent is referred to hereinafter as the length(L) of the dosage form. The extents of the projections of the dosageform onto the two other principal axes of inertia correspondrespectively to the height and width of the dosage form. “Elongate”means that the length of the dosage form is larger than its width or itsheight. The length of the dosage form is preferably more than 2.5 times,in particular 3 to 4.5 times, the width or height. The cross-sectionalarea means for the purposes of the present invention the area includedby the intersection line of the outer surface of the dosage form on aplane oriented perpendicular to the long axis of the solid dosage form.The two cross-sectional areas with maximal area lie opposite to oneanother at a distance of more than half the length of the dosage form inrelation to the cross-sectional areas with minimal area. The dosageforms according to the invention may have, for example at the level ofthe minimal cross-sectional area, an all-round “constriction”.Alternatively, a notch may be present on only one side of the tablet,whereas the opposite side is flat. A further possibility is for dosageforms according to the invention to be provided with notches on oppositesides.

With the dosage forms according to the invention there is normally areduction again in the area of the cross-sectional area toward one orboth ends after reaching the maximal cross-sectional area. However, thearea may also remain constant at this maximum value as far as the twoends of the dosage form after reaching the maximal cross-sectional area.In particular embodiments, the maximal cross section is reached only atthe ends of the dosage form.

The shape of the dosage form according to the invention makes itpossible to grip the dosage form satisfactorily with both hands. Theelongate shape with the outer-lying centers of mass results in afavorable torque action which facilitates division of the dosage forms.Because the cross-sectional area along which division of the dosage formtakes place is small, little “work for breaking” is necessary. Thedosage forms according to the invention can be divided into fragments ofaccurately predetermined size. This achieves satisfactory uniformity ofmass of the manually divided fragments of the dosage forms according tothe invention with a small standard deviation. The dosage formsaccording to the invention can also be further processed very wellwithout breaking. Because of the mass distribution predetermined by theshape of the dosage forms according to the invention, the dosage formsare substantially stable to axial stress and to lateral impact.

Preferred solid dosage forms according to the invention are those wherethe area of the minimal cross-sectional area (15) is no more than twothirds, in particular no more than 0.6 times the area of the maximalcross-sectional area.

The most important application of the present invention is for soliddosage forms which can be halved. With these dosage forms the minimalcross-sectional area is located in a plane of symmetry of the dosageform.

In preferred dosage forms according to the invention, at least one linerunning on the surface of the dosage form in the longitudinal directiondisplays a kink at the level of the minimal cross-sectional area. Thisdefines the place where the dosage form is intended to break moreaccurately. As a measure for the kink it is possible to define a notchangle which corresponds to the angle included by the two tangentialplanes placed on the surface of the dosage form on both sides of theminimal cross-sectional area. Preferred dosage forms according to theinvention have a notch angle of more than 90°, in particular of morethan 100°. The notch angle is generally less than 170°, preferably lessthan 162°. Any score which is present, as discussed hereinafter, is nottaken into account here.

It has been found that when breaking open dosage forms the tabletmaterial tends to break at sharp edges. Preferred dosage forms accordingto the invention therefore have essentially rounded edges. It isparticularly preferred for the dosage forms according to the inventionto have essentially no fillet in their equator. It is possible in thisway to minimize losses of active ingredient on manual division of thedosage forms.

For further facilitating divisibility, a score can be formed in thesurface of the dosage form according to the invention along theperiphery or along sections of the periphery of the minimalcross-sectional area. The depth of the score is preferably smallcompared with the depth of the constriction or of the notch caused bythe difference in the cross-sectional areas.

Solid dosage forms according to the invention can be produced by anysuitable process. However, it is particularly preferred for the dosageforms to be produced by a melt calendering. Melt calendering makes itpossible to produce dosage forms which have no pronounced fillet on thetablets. The fillet on tablets produced by conventional compressionrefers to the area formed by the wall of the die.

In melt calendering, at least one polymeric binder, at least one activeingredient and, where appropriate, conventional additives are mixed toform a plastic mixture, and this mixture is shaped in a calender withtwo counter-rotating molding rolls. At least one of the molding rollshas depressions to receive and shape the plastic mixture to dosageforms, and the depressions are designed so that solid dosage formsaccording to the above definition are obtained.

The dosage forms according to the invention generally comprise:

A) 0.1 to 90% by weight, in particular 0.1 to 60% by weight (based onthe total weight of the dosage form), of an active ingredient,

b) 10 to 99.9% by weight, in particular 40 to 99.9% by weight, of abinder, preferably polymeric binder and

c) where appropriate additives.

Suitable polymeric binders are polymers, copolymers, cellulosederivatives, starch and starch derivatives, for example:polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone (NVP) andvinyl acetate or vinyl propionate, copolymers of vinyl acetate andcrotonic acid, partially hydrolyzed polyvinyl acetate, polyvinylalcohol, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates),polyacrylates and polymethacrylates (Eudragit types), copolymers ofmethyl methacrylate and acrylic acid, polyacrylamides, polyethyleneglycols, polyvinylformamide (partially or totally hydrolyzed whereappropriate), cellulose esters, cellulose ethers, especiallymethylcellulose and ethylcellulose, hydroxyalkylcelluloses, inparticular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, inparticular hydroxypropylethylcellulose, cellulose phthalates, inparticular cellulose acetate phthalate and hydroxypropylmethylcellulosephthalate, and mannans, especially galactomannans. Of these,polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl esters,poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates),polyacrylates, polymethacrylates, alkylcelluloses andhydroxyalkylcelluloses are particularly preferred.

The polymeric binder must soften or melt in the complete mixture of allthe components in the range from 50 to 180° C., preferably 60 to 130° C.The glass transition temperature of the mixture must therefore be below180° C, preferably below 130° C. If necessary, it is reduced byconventional pharmacologically acceptable plasticizing auxiliaries. Theamount of plasticizer does not exceed 30% by weight, based on the totalweight of binder and plasticizer, in order to form drug forms which arestable on storage and show no cold flow. However, the mixture preferablycontains no plasticizer.

Examples of such plasticizers are:

long chain alcohols, ethylene glycol, propylene glycol, glycerol,trimethylolpropane, triethylene glycol, butanediols, pentanols such aspentaerythritol, hexanols, polyethylene glycols, polypropylene glycols,polyethylene/propylene glycols, silicones, aromatic carboxylic esters(e.g. dialkyl phthalates, trimellitic esters, benzoic esters,terephthalic esters) or aliphatic dicarboxylic esters (e.g. dialkyladipates, sebacic esters, azelaic esters, citric and tartaric esters),fatty acid esters such as glycerol monoacetate, glycerol diacetate orglycerol triacetate or sodium diethyl sulfosuccinate. The concentrationof plasticizer is generally from 0.5 to 15, preferably 0.5 to 5, % ofthe total weight of the mixture.

Conventional pharmaceutical excipients, whose total amount can be up to100% of the weight of the polymer, are, for example, extenders andbulking agents such as silicates or diatomaceous earth, magnesium oxide,aluminum oxide, titanium oxide, methylcellulose, sodiumcarboxymethylcellulose, talc, sucrose, lactose, cereal or corn starch,potato flour, polyvinyl alcohol, in particular in a concentration offrom 0.02 to 50, preferably 0.20 to 20, % of the total weight of themixture.

Mold release agents such as magnesium, zinc and calcium stearates,sodium stearylfumarate, talc and silicones, in a concentration of from0.1 to 5, preferably 0.1 to 3, % of the total weight of the mixture.Also suitable as mold release agents are animal or vegetable fats,especially in hydrogenated form and those which are solid at roomtemperature. These fats preferably have a melting point of 50° C. orabove. Triglycerides of C₁₂, C₁₄, C₁₆ and C₁₈ fatty acids are preferred.It is also possible to use waxes such as carnauba wax. These fats andwaxes may be admixed advantageously alone or together with mono- and/ordiglycerides or phosphatides, especially lecithin. The mono- anddiglycerides are preferably derived from the abovementioned fatty acidtypes. The total amount of fats, waxes, mono-, diglycerides and/orlecithins is from 0.1 to 30, preferably 0.1 to 5, % of the total weightof the composition for the particular layer;

flowability agents such as Aerosil (highly disperse silica) or talc;

dyes such as azo dyes, organic or inorganic pigments or dyes of naturalorigin, with preference for inorganic pigments in a concentration offrom 0.001 to 10, preferably 0.5 to 3, % of the total weight of themixture;

stabilizers such as antioxidants, light stabilizers, hydroperoxidedestroyers, radical scavengers, stabilizers against microbial attack.

It is also possible to add wetting agents, preservatives, disintegrantsand adsorbents, (cf., for example, H. Sucker et al., PharmazeutischeTechnologie, Thieme-Verlag, Stuttgart 1978).

Excipients include for the purpose of the invention substances forproducing a solid solution of the active ingredient. Examples of theseauxiliaries are pentaerythritol and pentaerythritol tetraacetate,polymers such as polyethylene oxide and polypropylene oxide and theirblock copolymers (poloxamers), phosphatides such as lecithin, homo- andcopolymers of vinylpyrrolidone, surfactants such as polyoxyethylene 40stearate, and citric and succinic acids, bile acids, sterols and othersas indicated, for example, in J. L. Ford, Pharm. Acta Helv. 61 (1986)pp.69-88.

Pharmaceutical excipients are also regarded as being additions of basesand acids to control the solubility of an active ingredient (see, forexample, K. Thoma et al., Pharm. Ind. 51 (1989) 98-101).

The only preconditions for the suitability of excipients are adequatetemperature stability and adequate compatibility of the excipient withthe active ingredient.

Active ingredients mean for the purpose of the invention all substanceswith a pharmaceutical effect and minimal side effects as long as they donot completely decompose under the processing conditions. They are, inparticular, active pharmaceutical ingredients (for humans and animals),active ingredients for plant treatment, insecticides, active ingredientsfor human and animal food, fragrances and perfume oils. The amount ofactive ingredient per dose unit and the concentration may vary withinwide limits depending on the activity and the release rate. The onlycondition is that they suffice to achieve the desired effect. Thus, theconcentration of active ingredient can be in the range from 0.1 to 95,preferably from 20 to 80, in particular 30 to 70, % by weight. It isalso possible to employ active ingredient combinations. Activeingredients for the purpose of the invention also include vitamins andminerals. The vitamins include the vitamins of the A group, the B group,which are meant besides B₁, B₂, B₆ and B₁₂ and nicotinic acid andnicotinamide to include also compounds with vitamin B properties such asadenine, choline, pantothenic acid, biotin, adenylic acid, folic acid,orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-inositoland lipoic acid, and vitamin C, vitamins of the D group, E group, Fgroup, H group, I and J groups, K group and P group. Active ingredientsfor the purpose of the invention also include therapeutic peptides.Plant treatment agents include, for example vinclozolin, apoxiconazoleand quinmerac.

The process according to the invention is suitable, for example, forprocessing the following active ingredients:

acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir,alfacalcidol, allantoin, allopurinol, alprazolam, ambroxol, amikacin,amiloride, aminoacetic acid, amiodarone, amitriptyline, amlodipine,amoxicillin, ampicillin, ascorbic acid, aspartame, astemizole, atenolol,beclomethasone, benserazide, benzalkoniumhydrochloride, benzocaine,benzoic acid, betamethasone, bezafibrate, biotin, biperiden, bisoprolol,bromazepam, bromhexine, bromocriptine, budesonide, bufexamac,buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine,carbidopa, carboplatin, cefachlor, cefadroxil, cefalexin, cefazolin,cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime,chloramphenicol, chlorhexidine, chlor-pheniramine, chlortalidone,choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride,cisplatin, clarithromycin, clavulanic acid, clomipramine, clonazepam,clonidine, clotrimazole, codeine, cholestyramine, cromoglycic acid,cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol,dextromethorphan, dextropropoxiphene, diazepam, diclofenac, digoxin,dihydrocodeine, dihydroergotamine, dihydroergotoxin, diltiazem,diphenhydramine, dipyridamole, dipyrone, disopyramide, domperidone,dopamine, doxocyclin, enalapril, ephedrine, epinephrine, ergocalciferol,ergotamine, erythromycin, estradiol, ethinylestradiol, etoposide,Eucalyptus globulus, famotidine, felodipine, fenofibrate, fenoterol,fentanyl, flavin-mononucleotide, fluconazole, flunarizine, fluorouracil,fluoxetine, flurbiprofen, folinic acid, furosemide, gallopamil,gemfibrozil, gentamicin, Gingko biloba, glibenclamide, glipizide,clozapine, Glycyrrhiza glabra, griseofulvin, guaifenesin, haloperidol,heparin, hyaluronic acid, hydrochlorothiazide, hydrocodone,hydrocortisone, hydromorphone, ipratropium-hydroxide, ibuprofen,imipenem, imipramine, indomethacin, iohexol, iopamidol,isosorbide-dinitrate, isosorbide-mononitrate, isotretinoin,itraconazole, ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol,lactulose, lecithin, levocarnitine, levodopa, levoglutamide,levonorgestrel, levothyroxine, lidocaine, lipase, lisinopril,loperamide, lorazepam, lovastatin, medroxyprogesterone, menthol,methotrexate, methyldopa, methylprednisolone, metoclopramide,metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol,morphine, multivitamin mixtures or combinations and mineral salts,N-methylephedrine, naftidrofuryl, naproxen, neomycin, nicardipine,nicergoline, nicotinamide, nicotine, nicotinic acid, nifedipine,nimodipine, nitrazepam, nitrendipine, nizatidine, norethisterone,norfloxacin, norgestrel, nortriptyline, nystatin, ofloxacin, omeprazole,ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol,penicillin G, penicillin V, pentoxifylline, phenobarbital,phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin,piroxicam, polymyxin B, povidone-iodine, pravastatin, prazepam,prazosin, prednisolone, prednisone, propafenone, propranolol,proxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril,ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside,saccharin, salbutamol, salcatonin, salicylic acid, selegiline,simvastatin, somatropin, sotalol, spironolactone, sucralfate, sulbactam,sulfamethoxazole, sulfasalazine, sulpiride, tamoxifen, tegafur,teprenone, terazosin, terbutaline, terfenadine, tetracycline,theophylline, thiamine, ticlopidine, timolol, tranexamic acid,tretinoin, triamcinolone-acetonide, triamterene, trimethoprim,troxerutin, uracil, valproic acid, vancomycin, verapamil, vitamin E,zidovudine.

Preferred active ingredients are ibuprofen (as racemate, enantiomer orenriched enantiomer), metoprolol, ketoprofen, flurbiprofen,acetylsalicylic acid, verapamil, paracetamol, nifedipine or captopril.

To produce the solid dosage forms, a plastic mixture of the components(melt) is prepared and then subjected to a shaping step. There arevarious ways of mixing the components and forming the melt. The mixingcan take place before, during and/or after the formation of the melt.For example, the components can be mixed first and then melted or bemixed and melted simultaneously. The plastic mixture is often thenhomogenized in order to disperse the active ingredient thoroughly.

However, it has proven preferable, especially when sensitive activeingredients are used, first to melt the polymeric binder and, whereappropriate, make a premix with conventional pharmaceutical additives,and then to mix in (homogenize), the sensitive active ingredient(s) inthe plastic phase in intensive mixers with very short residence times.The active ingredient(s) can for this purpose be employed in solid formor in solution or dispersion.

The components are generally employed as such in the production process.However, they can also be used in liquid form, i.e. as solution,suspension or dispersion.

Suitable solvents for the liquid form of the components are primarilywater or a water-miscible organic solvent or a mixture thereof withwater. However, it is also possible to use organic solvents which areimmiscible or miscible with water. Suitable water-miscible solvents are,in particular, C₁-C₄-alkanols, such as ethanol, isopropanol orn-propanol, polyols such as ethylene glycol, glycerol and polyethyleneglycols. Suitable water-immiscible solvents are alkanes such as pentaneor hexane, esters such as ethyl acetate or butyl acetate, chlorinatedhydrocarbons such as methylene chloride, and aromatic hydrocarbons suchas toluene and xylene. Another solvent which can be used is liquid CO₂.

The solvent used in the individual case depends on the component to betaken up and its properties. For example, pharmaceutical activeingredients are frequently used in the form of a salt which is generallysoluble in water. Water-soluble active ingredients can therefore beemployed as aqueous solution or, preferably, be taken up in the aqueoussolution or dispersion of the binder. The same applies to activeingredients which are soluble in one of the solvents mentioned, if theliquid form of the components used is based on an organic solvent.

It is possible where appropriate to replace melting by dissolving,suspending, or dispersing in the abovementioned solvents, if requiredand/or necessary with addition of suitable excipients such asemulsifiers. The solvent is then generally removed to form the melt in asuitable apparatus, for example an extruder. This will be comprised bythe term mixing hereinafter.

The melting and/or mixing takes place in an apparatus customary for thispurpose. Particularly suitable ones are extruders or containers whichcan be heated where appropriate and have an agitator, for examplekneaders (like those of the type to be mentioned below).

A particularly suitable mixing apparatus is one employed for mixing inplastics technology. Suitable apparatuses are described, for example, in“Mischen beim Herstellen und Verarbeiten von Kunststoffen”, H. Pahl,VDI-Verlag, 1986. A particularly suitable mixing apparatuses areextruders and dynamic and static mixers, and stirred vessels,single-shaft stirrers with stripper mechanisms, especially paste mixers,multishaft stirrers, especially PDSM mixers, solids mixers and,preferably, mixer/kneader reactors (for example ORP, CRP, AP, DTBsupplied by List or Reactotherm supplied by Krauss-Maffei or Ko-Kneadersupplied by Buss), trough mixers and internal mixers or rotor/statorsystems (for example Dispax supplied by IKA).

In the case of sensitive active ingredients it is preferable first for apolymeric binder to be melted in an extruder and then for the activeingredient to be admixed in a mixer/kneader reactor. On the other hand,with less sensitive active ingredients, a rotor/stator system can beemployed for vigorously dispersing the active ingredient.

The mixing apparatus is charged continuously or batchwise, depending onits design, in a conventional way. Powdered components can be introducedin a free feed, for example via a weigh feeder. Plastic compositions canbe fed in directly from an extruder or via a gear pump, which isparticularly advantageous if the viscosities and pressures are high.Liquid media can be metered in by a suitable pump unit.

The mixture obtained by mixing and/or melting the binder, the activeingredient and, where appropriate, the additive(s) ranges from pasty toviscous (plastic) or fluid and is therefore extrudable. The glasstransition temperature of the mixture is below the decompositiontemperature of all the components present in the mixture. The bindershould preferably be soluble or swellable in a physiological medium.

The steps of mixing and melting in the process can be carried out in thesame apparatus or in two or more separately operating apparatuses. Thepreparation of a premix can take place in one of the conventional mixingapparatuses described above. A premix of this type can then be feddirectly, for example, into an extruder and subsequently be extruded,where appropriate with the addition of other components.

It is possible in the process according to the invention to employ asextruders single screw machines, intermeshing screw machines or elsemultiscrew extruders, especially twin screw extruders, corotating orcounter-rotating and, where appropriate, equipped with kneading disks.If it is necessary in the extrusion to evaporate a solvent, theextruders are generally equipped with an evaporating section.Particularly preferred extruders are those of the ZSK series from Werner& Pfleiderer.

The resulting mixture is preferably solvent-free, i.e. it containsneither water nor an organic solvent.

The plastic mixture is subjected to a shaping in a calender withcounter-rotating molding rolls. The molding rolls have on their surfacesdepressions suitable for receiving and shaping the plastic mixture. Theplastic mixture is in this case introduced into the trough-like spacebetween the molding rolls, for example by means of a filling wedge. Twodepressions corresponding to one another on the molding rolls brieflymeet at the contact line of the molding rolls to form a tablet mold. Asrotation continues, the depressions diverge again and release the moldeddosage form. The depressions on the molding rolls are designed so thatthey correspond to the negative mold for one “half” of the dosage formsaccording to the invention. Depressions corresponding to one another onthe molding rolls may have the same shape or differ in shape. Thedepressions on one molding roll may have a uniform depth, whereas thedepressions on the other molding roll have different depths along thelong axis thereof. Alternatively, depressions in both molding rolls mayhave varying depths along the long axes. It is preferred for the longaxis of the depressions to be parallel to the axis of rotation of themolding rolls.

The resulting dosage forms can in a subsequent step be rounded,deflashed and/or provided with a coating by conventional processes.Suitable materials for film coatings are film formers, e.g.polyacrylates such as the Eudragit types, cellulose esters such as thehydroxypropylcellulose phthalates, and cellulose ethers such asethylcellulose, hydroxypropylmethylcellulose or hydroxypropylcellulose,where appropriate mixed with bulking agents, coloring pigments, wettingagents and plasticizers.

It is specifically possible for solid solutions to be formed. The term“solid solutions” is familiar to the skilled worker, for example fromthe literature cited at the outset. The active ingredient in solidsolutions of active ingredients in polymers is in the form of amolecular dispersion in the polymer.

The figures and the example hereinafter are intended to explain theinvention in detail.

FIG. 1 shows a cross section of a dosage form according to theinvention. The dosage form (10) has a long axis (11) and two ends (12,13). A first maximal cross-sectional area (14) is located near one end(12) and a second maximal cross-sectional area (16) is located near theother end (13). A cross-sectional area (15) with minimal cross sectionis located in the center of the tablet. The surface plane (17) lying inthe plane of the drawing has a kink (18) at the level of the minimalcross-sectional area (15). The tangential planes placed on the surfaceof the dosage form on both sides of the minimal cross-sectional area(15) include a notch angle (a). The depicted dosage form additionallyhas a score (19).

EXAMPLES Example 1

A pharmaceutical mixture was prepared in accordance with the followingformula:

Verapamil HCl 48.0% by weight; Hydroxypropylcellulose 31.5% by weight;Hydroxypropylmethylcellulose 17.5% by weight; Lecithin  3.0% by weight.

The pharmaceutical mixture was extruded in a twin-screw extruder underthe following conditions:

Temperature range 80-125° C. Screw speed 120 rpm Vacuum 100 mbar Meltflow rate 120 kg/h

The melt was passed into a molding calender with two molding rolls. Oneof the molding rolls had depressions of the type shown in FIG. 2 on itssurface. The second molding roll had on its surface elongate depressionswith a corresponding outline and a uniform depth. This resulted intablets as depicted in FIG. 3. They could be broken into two equalhalves easily and smoothly. The measured standard deviations for themanually divided dosage forms were in the region of 2% for a total massof 500 mg for the dosage forms. The standard deviation thus achieved isin a pharmaceutically acceptable range.

We claim:
 1. A solid, elongate dosage form with a long axis and with alength which is defined by projection of the ends of the dosage formonto the long axis, where a cross-sectional area oriented perpendicularto the long axis has an area which is variable along the long axis andincreases from a cross-sectional area which is located between the endsup to in each case a cross-sectional area which is located near one endfrom the maximal cross-sectional area which is located near the otherend is, projected on the long axis, more than half the length of thedosage from, and wherein the dosage from has no fillet in its equator.2. A dosage form as claimed in claim 1, wherein the distance of themaximal cross-sectional area located near one end from the maximalcross-sectional area located near the other end is, projected on thelong axis, more than 0.6 times the length.
 3. A dosage form as claimedin claim 1, wherein the area of the minimal cross-sectional area is notmore than two thirds of the area of the maximal cross-sectional area. 4.A dosage form as claimed in claim 3, wherein the area of the minimalcross-sectional area is no more than 0.6 times the area of the maximalcross-sectional area.
 5. A dosage form as claimed in claim 1, whereinthe minimal cross-sectional area lies in a plane of symmetry of thedosage form.
 6. A dosage form as claimed in claim 1, wherein at leastone surface line running in the longitudinal direction on the dosageform has a kink at the level of the minimal cross-sectional area.
 7. Adosage form as claimed in claim 6, wherein the dosage form has a notchangle of more than 90°.
 8. A dosage form as claimed in claim 1, whichhas rounded edges.
 9. A dosage form as claimed in claim 1, wherein ascore is formed in the surface of the dosage form along the periphery oralong sections of the periphery of the minimal cross-sectional area. 10.A process for producing dosage forms by molding an activeingredient-containing melt in a calender with two counter-rotatingmolding rolls, of which at least one has depressions to receive andshape the melt to dosage forms, wherein the molding roll(s) has (have)depressions designed so that dosage forms as claimed in claim 1 areobtained.